Prof. Enrique M. Ocio

“Marqués de Valdecilla” University Hospital & Biomedical Research Institute (IDIVAL), University of Cantabria, Santander - Spain

TREATMENT SEQUENCING IN A COMPLEX LANDSCAPETHE IMPORTANCE OF LONG-TERM PLANNING

GLOIXA2019-00011j. December 2019.

TREATMENT OF MM

ASCT, autologous stem cell transplantation; HD, high-dose; MM, multiple myeloma 1. Blokhin N et al. Ann NY Acad Sci 1958;68:1128–1132.

1844 1960 1970 1980 1990 2000 2003 2004 2013 2015 → 2019

Melphalan(Blokhin N et al.

Ann N Y Acad Sci 1958)1

Combination chemoVincristine

Doxorubicin Dexamethasone

MelphalanGlucocorticoids

(1969)

MrMcBean

1844

HD chemoASCT

Chemotherapy era

Targeted therapy era

Carfilzomib Pomalidomide

Thalidomide

Bortezomib Lenalidomide

PanobinostatDaratumumab

ElotuzumabIxazomib

Selinexor

MM treatment has completely changed in the past 15 years

HISTORICAL EVOLUTION OF MM PATIENTS

Survival of MM patients has at least doubled in the past 20 years

1. Kumar SK et al. Blood 2008;111:2516–2520; 2. Kumar SK et al. Leukemia 2014;28:1122–1128;3. Hernández JM et al. Br J Haematol 2004;127:159–164; 4. Mateos M-V et al. Haematologica 2014;99:221, abstract S644 (oral presentation). MM, multiple myeloma; OS, overall survival

Evolution of MM OS over the years1,2 Evolution of OS in elderly patients3,4

Melphalan-prednisoneMedian OS: 29.4 months3

706050403020100

1.0

0.8

0.6

0.4

0.2

0

Novel combinationsMedian OS: 60 months

0 20 40 60 80 100 120 140Time

0

0.2

0.4

0.6

0.8

1.0

Surv

ival

1971–761977–821983–881989–941994–002001–062006–10

Time

Surv

ival

THE AVAILABILITY OF NOVEL AGENTS AND THE IMPROVEMENT IN OUTCOME BRINGS NEW QUESTIONS

• What is our current objective in an MM patient?

• Are we curing a significant proportion of patients?

• Is MM already a chronic disease?

• Do we have to reserve drugs for eventual relapses?

• What is the optimal sequencing of therapy?

• Continuous or limited duration therapy?

MM, multiple myeloma

WHAT IS THE OBJECTIVE IN A PATIENT WITH NEWLY DIAGNOSED MM?

a) To relieve symptoms

b) To maintain the quality of life

c) To prolong the progression-free survival (PFS)

d) To prolong survival (OS)

e) To cure

MM, multiple myeloma; OS, overall survival; PFS, progression-free survival

VTD INDUCTION (+ ASCT) GIMEMA & GEM TRIALS

1. Rosinol L et al. Blood 2018;132:abstract 126; 2. Tacchetti P, et al. Blood 2018;132:abstract 128.

ASCT, autologous stem cell transplantation; CI, confidence interval; HR, hazard ratio; NS, not significant; OS, overall survival; PFS, progression-free survival; (V)TD, (bortezomib)-thalidomide-dexamethasone

PETHEMA GEM0511

Median follow-up: 115 monthsGIMENA2

Median follow-up: 124 months

PFS VTD: 34% at 10 years

OS VTD: 60% at 10 years

p=0.01

mPFS VTD: 52 months24% PFS @ 10 years

1.0

0Time (months)

PFS

(%

)

20 40 60 80 100 120 140

0.8

0.6

0.4

0.2

0.0

mOS VTD: 128 months51% OS @ 10 years

p=NS

1.0

0

OS

(%)

20 40 60 80 100 120 140

0.8

0.6

0.4

0.2

0.0

Time (months)

1.00

0Months

PFS

pro

bab

ility

0.75

0.50

0.25

0.00

HR 0.62 [CI:0.50–0.77]P<0.0001

12 24 36 48 60 72 84 96 108 120

VTDTD

34%

17%

59.640.7

1.00

0Months

OS

pro

bab

ility

0.75

0.50

0.25

0.00

HR 0.68 [CI:0.51–0.90]P=0.007

12 24 36 48 60 72 84 96 108 120

46%

60%

110

AS THE MAJORITY OF PATIENTS WILL NOT BE CURED…

do we have to reserve drugs for eventual relapses

or

should we use everything we have frontline?

PERCENTAGE OF PATIENTS REACHING EACH LINE OF THERAPY

*Data from 4,997 patient charts in Belgium, France, Germany, Italy, Spain, Switzerland, and the UK.The proportion of patients who had received each line are from the cross-sectional review;data on durations of treatment and treatment-free intervals are from the retrospective review.1L-5L, first line-fifth line treatment; CI, confidence interval; m, month/s 1. Yong K et al. Br J Haematol 2016;175:252–264.

We should use the best potential option in each line of therapy, when both the patient and the disease are in the best situation

100%

95%

61%

38%

15%

1%

Mean (95% CI): diagnosis, 2 m (1.60, 2.40); 1L, 8 m (7.74, 8.26); 1L maintenance, 9 m (7.78, 10.22)

Mean (95% CI): 2L–3L, 11 m (10.22, 11.78); 3L, 8 m (7.63, 8.37)

Mean (95% CI): 1L–2L, 16 m (15.0, 17.0); 2L 9 m (8.64, 9.36)

Mean (95% CI): 3L–4L, 7 m (5.9, 8.1); 4L, 6 m (5.5, 6.5)

Mean (95% CI): 4L–5L, 3 m (1.8, 4.2); 5L, 4 m (3.15, 4.85)

Median durations in months shown

Start1L

End 1L induction End 1L maintenance

Start2L

Start4L

Start5L

End 2L

End 3LStart 3L

End 4L

End 5L

1L

2L

3L

4L

5L

1 m 6 m 6 m

5 m 6 m

3 m

1 m 4 m

Active treatmentTreatment-free interval

Maintenance treatment

5 m

Diagnosis

10 m 7 m

Proportion of patients reaching this line of therapy (%)

ESMO CLINICAL PRACTICE GUIDELINES FOR THE MANAGEMENT OF NDMM

Moreau P et al. Ann Oncol 2017;28 Suppl 4:iv52-61.

Eligibility for ASCT

Yes No

First optionVMP or Rd or RVd

Second optionMPT or VCd

Other optionsCTd, MP, Benda-Pred

Induction3-drug regimens

VTdVCdPAdRVd

Melphalan 200 mg/m2

followed by ASCT

Lenalidomide maintenance

Dara-VMPDara-RdKRd

Dara-VTdDara-Rd

Continuous lenalidomide and/or Dara

+/- proteasome inhibitor or Dara

ASCT, autologous stem cell transplantation; Benda-Pred, bendamustine-prednisone; CTd, cyclophosphamide-thalidomide-dexamethasone; Dara, daratumumab; ESMO, European Society for Medical Oncology; NDMM, newly diagnosed multiple myeloma; KRd, carfilzomib-lenalidomide-dexamethasone; MP(T), melphalan-prednisone-(thalidomide); PAd, bortezomib-doxorubicin-dexamethasone; R(V)d, lenalidomide-(bortezomib)-dexamethasone; VCd/VTd/VRd, bortezomib-cyclophosphamide/thalidomide/lenalidomide-dexamethasone; VMP, bortezomib-melphalan-prednisone

STRATEGIES AT RELAPSE:HOW TO MAKE THE RIGHT CHOICE?

Efficacy of previoustreatments

(Len refractory)

Optimize the best treatment in the best situation and combinationsWhat do we have left for subsequent therapies?

Should we consider upfront the potential 2nd or 3rd lines? How far ahead are we able to plan treatment?

Biomarkers

CostToxicity of previous treatments

Convenience of administration

Further options

Sequential treatment

CytogeneticsType of relapse(aggressive vs non-aggressive)

Len, lenalidomide

STRATEGIES AT RELAPSE:HOW TO MAKE THE RIGHT CHOICE?

To Lenor

not to Len?

Len, lenalidomide

TREATMENT POSSIBILITIES AT RELAPSE

2nd ASCT

KRd

IRd

Dara-Rd

Rd naïve/sensitive Rd exposed/refractory

Oral Not so good at 1st relapse after ASCT

CV history … Care with carfilzomibGI problems … Care with ixazomibCOPD or asthma … Care with dara

First relapses

Elo-RdEfficacy

Prior PI refractoryConvenience (oral)

Cytogenetics (all work)Age and comorbidities Kd + Cyclo

Dara-Vd

Not in HR Weekly & KCd?

Better 1st

relapse Pano-Vd Pom-Vd

Phase 3 trials

1. Dimopoulos MA et al. N Engl J Med 2016;375:1319–1331; 2. Bahlis NJ et al. Blood 2018;132:abstract 1996;3. Kaufman JL et al. Blood 2019;134:abstract 1866; 4. Dimopoulos MA et al. Haematologica 2017;102:108–109;

5. Stewart AK et al. N Engl J Med 2015;372:142–152; 6. Siegel DS et al. J Clin Oncol 2018;36:728–734;7. Lonial S et al. N Engl J Med 2015;373:621–631; 8. Dimopoulos MA et al. Cancer 2018;124:4032–4043;

9. Moreau P et al. N Engl J Med 2016;374:1621–1634.

Efficacy Dara-Rd vs Rd1–4

POLLUX

KRd vs Rd5,6

ASPIRE

Elo-Rd vs Rd7,8

ELOQUENT-2

IRd vs Rd9

TOURMALINE-MM1

PFS (months) 45.8 vs 17.5 m 26.3 vs 17.6 m 19.4 vs 14.9 m 20.6 vs 14.7 m

HR (95% CI) 0.43 (0.35–0.54) 0.69 (0.57–0.83) 0.71 (0.59–0.86) 0.74 (0.59–0.94)

ORR, % 93 87 79 78≥ CR, % 57 (MRD 30%) 32 5 14DOR, months NE 28.6 21 20.5

OS HR (95% CI) 0.63 (0.42–0.95)0.79 (0.67–0.95)

48 vs. 40 m

0.78 (0.63–0.96)

48 vs 40 mNE

ASCT, autologous stem cell transplantation; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CR, complete response; CV, cardiovascular; Cyclo, cyclophosphamide; Dara, daratumumab; DOR, duration of response; Elo, elotuzumab; GI, gastrointestinal; HR, hazard ratio; IRd, ixazomib-lenalidomide-dexamethasone; K(C)d, carfilzomib-(cyclophosphamide)-dexamethasone; m, months; MRD, minimal residual disease; NE, not estimable; ORR, overall response rate; OS, overall survival; Pano, panobinostat; PFS, progression-free survival; PI, proteasome inhibitor; Pom, pomalidomide; Rd, lenalidomide-dexamethasone; Vd, bortezomib-dexamethasone

TREATMENT POSSIBILITIES AT RELAPSE

2nd ASCT

KRd

IRd

Dara-Rd

Rd naïve/sensitive Rd exposed/refractory

Oral Not so good at 1st relapse after ASCT

First relapses

Elo-RdEfficacy

Prior PI refractoryConvenience (oral)

Cytogenetics (all work)Age and comorbidities

Efficacy Dara-Rd vs Rd1–4

POLLUX

KRd vs Rd5,6

ASPIRE

Elo-Rd vs Rd7,8

ELOQUENT-2

IRd vs Rd9

TOURMALINE-MM1

PotencyConvenience (oral, visits, time)High riskPrior PI exposed/refractory

OtherCare with

COPD/asthmaCare with CV

Worst 1st relapse after ASCT

Phase 3 trials

*Approved population: Prior bortezomib + IMiDs ≥2 prior lines

1. Dimopoulos MA et al. N Engl J Med 2016;375:1319–1331; 2. Bahlis NJ et al. Blood 2018;132:abstract 1996;3. Kaufman JL et al. Blood 2019;134:abstract 1866; 4. Dimopoulos MA et al. Haematologica 2017;102:108–109;

5. Stewart AK et al. N Engl J Med 2015;372:142–152; 6. Siegel DS et al. J Clin Oncol 2018;36:728–734;7. Lonial S et al. N Engl J Med 2015;373:621–631; 8. Dimopoulos MA et al. Cancer 2018;124:4032–4043;

9. Moreau P et al. N Engl J Med 2016;374:1621–1634.

CV history … Care with carfilzomibGI problems … Care with ixazomibCOPD or asthma … Care with dara

ASCT, autologous stem cell transplantation; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; Dara, daratumumab; Elo, elotuzumab; GI, gastrointestinal; IMiDs, immunomodulatory drugs; IRd, ixazomib-lenalidomide-dexamethasone; KRd, carfilzomib-lenalidomide-dexamethasone; PI, proteasome inhibitor; Rd, lenalidomide-dexamethasone

TREATMENT POSSIBILITIES AT RELAPSE

2nd ASCT

KRd

IRd

Dara-Rd

Rd naïve/sensitive Rd exposed/refractory

Oral Not so good at 1st relapse after ASCT

First relapses

Elo-RdEfficacy

Prior PI refractoryConvenience (oral)

Cytogenetics (all work)Age and comorbidities Kd + Cyclo

Dara-Vd

Not in HR Weekly & KCd?

Better 1st

relapse Pano-Vd Pom-Vd

Pom-Vd7,8

70% Len refractory, PFS 9.5 m64% Len refractory after 1 prior line, PFS 17.84 mDara-Vd:9 7.8 mKd (ENDEAVOR & CHAMPION):10

9.6 m, 15.6 m in Len refractory as 1st line

1. Dimopoulos MA et al. Lancet Oncol 2016;17:27–38; 2. Dimopoulos MA et al. Lancet Oncol 2017;18:1327–1337; 3. Palumbo A et al. N Engl J Med 2016;375:754–766; 4. Mateos M-V et al. Blood 2018;132:abstract 3270; 5. San Miguel JF et al. Lancet Oncol

2014;15:1195–1206; 6. Richardson PG et al. Blood 2016;127:713–721; 7. Richardson PG et al. Lancet Oncol 2019;20:781–794; 8. Dimopoulos MA et al. HemaSphere 2019;3:250–251; 9. Usmani SZ et al. Blood 2018;132:abstract 3288;

10. Mateos MV et al. Blood 2018;132:abstract 1963.

Efficacy Kd vs Vd1,2

ENDEAVOR (n=929)

Dara-Vd vs Vd3,4

CASTOR (n=498)

Pano-Vd vs Vd5,6

PANORAMA-1 (n=147)*

Pom-Vd vs Vd7

OptimisMM (n=559)

PFS (months) 18.7 vs 9.4 m 16.7 vs 7.1 m 12.5 vs 4.7 m 11.2 vs 7.1

HR (95% CI) 0.53 (0.44 – 0.65) 0.31 (0.25 – 0.40) 0.47 (0.31-0.72) 0.61 (0.49-0.77)

ORR, % 77 85 59 82

≥ CR, % 1330 (MRD-negative 14%)

(sustained MRD 3%)16

OS HR (95% CI) 0.79 (0.65–0.96)

47.6 vs. 40 m0.98

Other Weekly? / + Cyclo?No data on Len refractory

Better in 1 prior lineNot used

*Approved population: Prior bortezomib + IMiDs ≥2 prior lines

Phase 3 trials

CV history … Care with carfilzomibGI problems … Care with ixazomibCOPD or asthma … Care with dara

ASCT, autologous stem cell transplantation; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CR, complete response; CV, cardiovascular; Cyclo, cyclophosphamide; Dara, daratumumab; Elo, elotuzumab; GI, gastrointestinal; HR, hazard ratio; K(C/R)d, carfilzomib-(cyclophosphamide/lenalidomide)-dexamethasone; Len, lenalidomide; m, months; ORR, overall response rate; OS, overall survival; Pano, panobinostat; PFS, progression-free survival; PI, proteasome inhibitor; Pom, pomalidomide; Pom-Vd, pomalidomide-bortezomib-dexamethasone; Rd, lenalidomide-dexamethasone; refr., refractory; Vd, bortezombi-dexamethasone

TREATMENT POSSIBILITIES AT RELAPSE

2nd ASCT

KRd

IRd

Dara-Rd

Rd naïve/sensitive Rd exposed/refractory

Oral Not so good at 1st relapse after ASCT

First relapses

Elo-RdEfficacy

Prior PI refractoryConvenience (oral)

Cytogenetics (all work)Age and comorbidities Kd + Cyclo

Dara-Vd

Not in HR Weekly & KCd?

Better 1st

relapse Pano-Vd Pom-Vd

Phase 3 trials

VRd Cyclo-Rd VCdCost or availability concerns

Subsequent relapses

Daratumumab

Double refractory to PI & IMID Dara-Kd Dara-Pom-d

Chemo+Allo Immuno-therapy

Isa-Pom-d

Pom-dex+/- Cyclo / Bort

Dara-Pom-d Elo-Pom-d

MelflufenVenetoclaxSelinexor

Iberdomide

BCMA-ADCBiTe: BCMA-CD3

BCMA-CAR-T

CV history … Care with carfilzomibGI problems … Care with ixazomibCOPD or asthma … Care with dara

Allo, allogeneic; ASCT, autologous stem cell transplantation; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; Cyclo, cyclophosphamide; Dara, daratumumab; Elo, elotuzumab; GI, gastrointestinal; HR, hazard ratio; IMiD, immunomodulatory drug; Isa, isatuxaimb; K, carfilzomib; KCd, carfilzomib-cyclophosphamide-dexamethasone; Kd, carfilzomib-dexamethasone; Pano, panobinostat; PI, proteasome inhibitor; Pom-dex, pomalidomide-dexamethasone; Rd, lenalidomide-dexamethasone; refr., refractory; V(C/R)d, bortezomb-(cyclophosphamide/lenalidomide)-dexamethasone

CONCLUSIONS

• At every line of therapy we should try to administer the best potential treatment

– Depends on age, fitness, comorbidities, regional access, patient preference

– Many patients (mainly elderly) will not have a second chance

– In subsequent relapses, both the patient and disease will be worse

– After 3rd line, few new options available, and responses and PFS are unsatisfactory

• Subsequent treatments will mainly depend on the efficacy and toxicity of prior ones

– Now most patients are Len-exposed and few Dara-exposed

– Now the concern is Len-refractory patients

Is this the same with 25 mg versus 10 mg? Or early versus late progression? Len until progression?

– In the future, Dara refractoriness after 1st line will be a challenge

Dara, daratumumab; Len, lenalidomide; PFS, progression-free survival

ACKNOWLEDGMENTS

Cancer Research Center

University Hospital

Jesús F. San Miguel

University Hospital “Marqués de Valdecilla” & Valdecilla Biomedical Research Institute

University of Cantabria

University Hospital of Salamanca